This invention relates to the chiral synthesis of (2S)-tetrahydro-2.alpha.-methyl-6-oxo-4.beta.-amino-2H-pyran-3.alpha.-carb oxylic acid (I) which is useful in the synthesis of thienamycin (III). ##STR2##
The total, stereo-controlled synthesis of thienamycin via lactone I has previously been described in co-pending commonly assigned U.S. Patent Application Ser. No. 112,020 Filed Jan. 14, 1980. However, this prior procedure produced I in a racemic state which required resolution, a step which resulted in a more than 50% loss in overall yield because the previous procedure produced 50% of the wrong enantiomer, which of course had to be discarded. The process of the present invention avoids the formation of the wrong enantiomer and hence is potentially higher-yielding and more economical.
The process of the present invention proceeds via the stereoselective reduction of a 2-acetyl-3-substituted amino-2-pentenedioic-acid diester (II). ##STR3## wherein R is (R)-.alpha.-methylbenzyl, or (S)-.alpha.-methylbenzyl, or esters of (R)- and (S)-.alpha.-carboxybenzyl, for example: --CH(C.sub.6 H.sub.5)CO.sub.2 R.sup.n wherein R.sup.n is alkyl having 1-6 carbon atoms or aralkyl, such as methyl, ethyl, benzyl and the like. The R.sup.1 ester moieties may be the same or different and are typically lower alkyl having from one to six carbon atoms such as methyl, ethyl, isopropyl, or the like, phenyl, or arylalkyl such as benzyl. The nature of the stereospecific reduction of (II) to give (I) to give thienamycin is discussed below.